A major goal of cardiac research is to develop the means to repair diseased or damaged hearts with newly generated myocardial tissue. A longstanding paradigm of cardiovascular biology was that the myocardium of the adult mammalian heart is postmitotic. In recent years, this concept has been challenged by reports that at least a limited amount of cardiomyocyte regeneration occurs during adulthood, although this is still an unresolved scientific issue. This proposal will take a novel approach to studying the cell biology and cellular regeneration of the adult myocardium. We propose to use the transgenic lacZ reporter mouse tgG6/lacZ, which has been shown to identify cardiac progenitors and newly formed myocytes in the embryonic heart, for the study of the adult heart. Our initial experiments suggest that this transgenic mouse will be a useful model for examining the cellular regeneration and the phenotypic heterogeneity of the myocardium. Four interrelated aims are proposed that will examine the distributions of cardiac progenitors and newly formed myocytes, the prevalence of fetal-like myocyte phenotypes within the healthy heart, the phenotypic changes that occur within the myocardium in response to injury, and how the biology of the myocardium changes during the aging process. We hypothesize that placing the adult heart under the scrutiny of myocardial lineage transgenic reporter mice, as has been done for the embryonic heart, will also elicit new and important insights on the biology of the adult myocardium and pathology of the diseased heart. PUBLIC HEALTH RELEVANCE In this proposal, we plan to utilize research tools that have been very successful in uncovering novel and important information about cardiac muscle regeneration in the embryo and apply them to the study of the adult heart. We hypothesize that placing the adult heart under the scrutiny of transgenic mice that labels newly formed cardiac muscle cells, as has been done for the embryonic heart, will also elicit new and important insights on the adult myocardium and insights into future medical therapy.